Psoriasis is one of the most widespread chronic diseases. It affects about two percent of the adult white population, the most severe symptoms being shown by patients in the age groups between twenty and fifty years old.
Psoriasis is characterized by a greatly accelerated rate of epidermal turnover. Instead of the normal period of 28 days from the time of cell division in the basal layers until the cell is shed from the stratum corneum, in psoriasis this takes only about four days.
The causes and mechanism of development of psoriasis are unknown, and for this reason a completely effective treatment for this ailment does not yet exist. A great number of approaches have been tried, from the very old, based on natural tars, to the more modern using steroids, sporalene, etc. Tars are messy to apply and have only a limited effect. Their combination with sulfur and salicylic acid are not much better. This therapy is frequently supplemented by the use of ultraviolet (UV) radiation, either natural (sunshine) or artificial (lamps). Other compounds used are: steroids, azaribine, methotrexate, psoralen, and retinoic acid derivatives. All of these have a rather high toxicity and their long term use may result in noxious side effects.
A possible approach to the therapy of the disease is to try to influence cellular metabolism, which obviously is much more active in the psoriatic cells than in the normal ones.
A few years ago, a new treatment was proposed. This is based on the use of fumaric acid in the form of its simple mono- or diesters or its metal salts, based on the theory that in the psoriatic portions of the skin there exists an unbalance in the dicarboxylic-acids cycle conducive to lower levels of fumarate. This theory seems to be confirmed by the fact that some amino acids, such as glycine, are present in lower quantities in the psoriatic skin, compared to their content in normal skin. Since these amino acids are also derived from the dicarboxylic-acids cycle, their presence in lower quantities is an added corroboration to the above theory.
The treatment of psoriasis by fumaric esters and related compounds has been described with increasing interest. C. Nieboer et al., J. Am. Acad. Dermatol. 20, 601-8 (1989); W. M. Nygteren-Huying et al., Fourth International Symposium on the treatment of psoriasis and psoriasis-arthritis, Jerusalem, Israel (March 1989). There are at present thousands of patients being treated with tablets containing dimethyl fumarate as the main active ingredient. Although this treatment has shown some success, there are some serious questions about the side-effects caused by the prolonged use of the fumarate esters. The short term use of these compounds can also result in the occurrence of hot flashes, nausea and irritation of the gastrointestinal system.
A number of patent applications deal with the use of fumarate esters and salts for the treatment of psoriasis. GP 2530372 (13.1.77) describes the use of fumaric acid, fumarate esters, such as monoethyl and monomethyl fumarate, dimethyl fumarate, and some salts of the monoesters such as manganese, calcium, zinc, iron, etc. All of these can be mixed with other ingredients such as tartaric acid, citric acid, sugar, and inert fillers. Some of these formulations are for internal use and some for external (topical) application. Related applications, GP 2840498 (10.4.80) and GP 2901452 (17.7.80), describe the addition of glycine, 1-methionine, and 1-cysteine to the above mixtures of fumarate esters and salts. A recent European patent, 0188749 A2 (30.7.86) claims the use of fumarate esters of alcohols having one to eight carbon atoms, esters of higher alcohols (C6-C24), metal salts of the monoesters, and esters of diols, glycerol, and other hydroxyl-containing compounds. Another patent, GP DE 3232883 A1 mentions the preparation of salts of fumaric acid with various caffein-8-ethers. The salts are crystalline and can be used for the preparation of tablets, capsules, etc., in combination with metal salts of fumaric esters, as mentioned before, and also with the optional addition of amino acids such as cysteine and methionine, and of vitamin C.
There exist serious problems as to the use of the above in the therapy of psoriasis. Short-chain fumarate esters are in general irritating materials which frequently produce an unpleasant acidosis effect upon ingestion. Metal salts of the half esters are quickly converted in the stomach into the free acid and the respective metal hydrochloride. The same happens with the caffein-ether salt. The esters are liquid at room temperature and in order to convert them to tablets they have to be adsorbed on, or mixed with, a rather large quantity of inert carrier. Furthermore, they have a strong characteristic odor and their toxicology has not been studied extensively. According to a study made with mice, monoethyl fumarate and dimethyl fumarate given per os had an LD.sub.50 above 100 mg/kg. Monoethyl fumarate, given intraperitoneally, was more toxic (W. Raab, H&G Nr. 10 (1984)). These fumarate esters are highly irritating to the skin and can produce contact urticaria (A. Lahti et al., Contact Dermatitis 12, 139-140 (1985)).
PCT International Application No. PCT/US88/02941 describes new derivatives of fumaric acid which, while retaining the effectiveness of fumarate, exhibit reduced side effects.
To summarize: mono and diesters of fumaric acid have been shown to be effective in the treatment of psoriasis, as the experience with several thousand patients indicates (see, for instance: Schafer G. Fumarsauretherapie der Psoriasis, Arztliche Praxis 30, 61 p. 1757-58 (1978); also, Selecta 15, p. 1260-61 (1984)). The esters are irritating to the digestive system and to the skin and their toxicology has not been clearly established; they are also difficult to formulate as tablets.
In biochemical terms the closest molecules to fumarate are maleate and malate.
Maleate is known to be ineffective in the treatment of psoriasis and is also more toxic than fumarate. On the other hand, malate and fumarate differ by hydrolysis of the unsaturated bond of fumarate. In the cell, fumarate is hydrated to malate by means of the enzyme fumarate hydratase (fumarase). The reaction is freely reversible with practically no energy barrier. G. Zubay, Biochemistry, 2nd Edition, p. 334, Addison-Wesley Publishing Co. (Reading, Mass.) (1984).
Studies in vitro have also shown the biochemical similarity between fumarate and malate. C. Sreeramula Chetty et al., Arch. Int. Physiol. Biochem. 90(4), p. 293-6 (1982). If psoriasis is related to a defect in the tricarboxylic acid cycle which can be compensated by the accumulation of fumarate, it is quite possible that malate could also have a similar effect. Moreover, malate also converts to oxaloacetate in the energy-generating tricarboxylic acid cycle, and it might be more effective in this respect.
Recent studies have shown that in psoriatic skin the content of glycine and serine is about twenty-five percent lower than in normal skin (Thaler et al., J. Invest. Dermatol. 75, 156-158 (1980); also, Steinert et al., Biochemistry of Normal and Abnormal Epidermal Differentiation, eds. I. A. Bereinstein and M. Seiji, Tokyo University Press, p. 391-406 (1980)). This deficiency may be related to the malate or fumarate imbalance or to other unknown causes. The addition of glycine as such, to such formulations, cannot contribute much to the therapeutic effect since this water-soluble material will be quickly incorporated into the general metabolic processes, so, at best, its value will be like an added food.